THIOL-DERIVATIZED NUCLEOSIDES AND OLIGONUCLEOSIDES

Abstract: Nucleosides and linked nucleosides functionalized to include alkylthiol chemical functionality at ribofuranosyl positions, nucleosidic base positions, or on internucleoside linkages. In certain embodiments, the compounds of the invention further include steroids, reporter molecules, reporter enzymes, lipophilic molecules, peptides or proteins attached to the nucleosides through the alkylthio group.

Description: THIOL-DERIVATIZED NUCLEOSIDES AND OLIGONUCLEOSIDES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of application serial number PCT/US92/09196, filed October 23, 1992, which is a continuation-in-part of application serial number 782,374, filed October 24, 1991, which is a continuation-in-part of application serial number 463,358, filed January 11, 1990, and of application serial number 566,977, filed August 13, 1990. The entire disclosures of each of these applications, which are assigned to the assignee of this application, are incorporated herein by reference. FIELD OF THE INVENTION This application is directed to nucleosides, oligonucleo- tides and oligonucleosides functionalized to include alkylthiol chemical functionalities, and derivatives thereof. In certain embodiments, the compounds of the invention further include steroids, reporter molecules, reporter enzymes, lipophilic molecules, peptides or proteins attached to the nucleosides, oligonucleotides or oligonucleosides through the alkylthio group. BACKGROUND OF THE INVENTION Messenger RNA (mRNA) directs protein synthesis. Antisense methodology is the complementary hybridization of relatively short oligonucleotides to mRNA or DNA such that the normal, essential functions of these intracellular nucleic acids are disrupted. Hybridization is the sequence-specific hydrogen bonding via Watson-Crick base pairs of oligonucleo- tides to RNA or single-stranded DNA. Such base pairs are said to be complementary to one another. The naturally occurring events that provide the disruption of the nucleic acid function, discussed by Cohen in Oligonucleotides : Antisense Inhibi tors of Gene Expression, CRC Press, Inc., Boca Raton, Florida (1989) are thought to be of two types. The first, hybridization arrest, denotes the terminating event in which the oligonucleotide inhibitor binds to the target nucleic acid and thus prevents, by simple steric hindrance, the binding of essential proteins, most often ribosomes, to the nucleic acid. Methyl phosphonate oligonucleotides (Miller, et al., Anti -Cancer Drug Design 1987 , 2, 117) and cu-anomer oligonucleotides are the two most extensively studied antisense agents which are thought to disrupt nucleic acid function by hybridization arrest. The second type of terminating event for antisense oligo¬ nucleotides involves the enzymatic cleavage of the targeted RNA by intracellular RNase H. A 2' -deoxyribofuranosyl oligonucleo¬ tide or oligonucleotide analog hybridizes with the targeted RNA and this duplex activates the RNase H enzyme to cleave the RNA strand, thus destroying the normal function of the RNA. Phosphorothioate oligonucleotides are -the most prominent example of an antisense agent that operates by this type of antisense terminating event. Considerable research is being directed to the application of oligonucleotides and oligonucleotide analogs as antisense agents for diagnostics, research reagents and potential therapeutic purposes. At least for therapeutic purposes, the antisense oligonucleotides and oligonucleotide analogs must be transported across cell membranes or taken up by cells to express activity. One method for increasing membrane or cellular transport is by the attachment of a pendant lipophilic group. Ramirez, et al . , J. Am . Chem . Soc . 1982, 104 , 5483, introduced the phospholipid group 5' -O- (1, 2-di-O-myristoyl-sn- glycero-3-phosphoryl) into the dimer TpT independently at the 3' and 5' positions. Subsequently Shea, et al . , Nuc. Acids Res . 1990, 18, 3777, disclosed oligonucleotides having a 1,2- di-O-hexyldecyl-rac-glycerol group linked to a 5' -phosphate on the 5' -terminus of the oligonucleotide. Certain of the Shea, et. al . authors also disclosed these and other compounds in patent application PCT/US90/01002. A further glucosyl phospholipid was disclosed by Guerra, et al . , Tetrahedron Letters 1987, 28 , 3581. In other work, a cholesteryl group was attached to the inter-nucleotide linkage between the first and second nucleotides (from the 3' terminus) of an oligonucleotide. This work is disclosed in United States patent 4,958,013 and further by Letsinger, et al . , Proc . Natl . Acad . Sci . USA 1989, 86, 6553. The aromatic intercalating agent anthraquinone was attached to the 2' position of a sugar fragment of an oligonucleotide as reported by Yamana, et al . , Bioconjugate Chem. 1990, 1, 319. Lemairte, et al . , Proc . Natl . Acad. Sci . USA 1986, 84 , 648; and Leonetti, et al . , Bioconjugate Chem. 1990, 1, 149. The 3' terminus of the oligonucleotides each include a 3'- terminal ribose sugar moiety. The poly(L-lysine) was linked to the oligonucleotide via periodate oxidation of this terminal ribose followed by reduction and coupling through a N- morpholine ring. Oligonucleotide-poly(L-lysine) conjugates are described in European Patent application 87109348.0. In this instance the lysine residue was coupled to a 5' or 3' phosphate of the 5' or 3' terminal nucleotide of the oligonucleotide. A disulfide linkage has also been utilized at the 3' terminus of an oligonucleotide to link a peptide to the oligonucleotide as is described by Corey, et al . , Science 1987, 238, 1401; Zuckermann, et al . , J. Am . Chem. Soc . 1988, 110, 1614; and Corey, et al . , J. Am. Chem . Soc . 1989, 111 , 8524. Nelson, et al . , Nuc . Acids Res . 1989, 17, 7187 describe a linking reagent for attaching biotin to the 3'-terminus of an oligonucleotide. This reagent, N-Fmoc-O-DMT-3-amino-l,2- propanediol is now commercially available from Clontech Laboratories (Palo Alto, CA) under the name 3'-Amine on. It is also commercially available under the name 3' -Amino-Modifier reagent from Glen Research Corporation (Sterling, VA) . This reagent was also utilized to link a peptide to an oligonucleotide as reported by Judy, et al . , Tetrahedron Letters 1991, 32, 879. A similar commercial reagent (actually a series of such linkers having various lengths of polymethylene connectors) for linking to the 5' -terminus of an oligonucleotide is 5' -Amino-Modifier C6. These reagents are available from Glen Research Corporation (Sterling, VA) . These compounds or similar ones were utilized by Krieg, et al . , Antisense Research and Development 1991, 1 , 161 to link fluo- rescein to the 5' -terminus of an oligonucleotide. Other compounds of interest have also been linked to the 3'-terminus of an oligonucleotide. Asseline, et al . , Proc. Natl . Acad. Sci . USA 1984, 81 , 3297 described linking acridine on the 3'- terminal phosphate group of an poly (Tp) oligonucleotide via a polymethylene linkage. Haralambidis, et al. , Tetrahedron Letters 1987, 28, 5199 report building a peptide on a solid state support and then linking an oligonucleotide to that peptide via the 3' hydroxyl group of the 3' terminal nucleotide of the oligonucleotide. Chollet, Nucleosides & Nucleotides 1990, 9, 957 attached an Aminolink 2 (Applied Biosystems, Foster City, CA) to the 5' terminal phosphate of an oligonucleotide. They then used the bifunctional linking group SMPB (Pierce Chemical Co., Rockford, II) to link an interleukin protein to the oligonucleotide. An EDTA iron complex has been linked to the 5 position of a pyrimidine nucleoside as reported by Dreyer, et al . , Proc . Natl . Acad. Sci . USA 1985, 82, 968. Fluorescein has been linked to an oligonucleotide in the same manner as reported by Haralambidis, et al . , Nucleic Acid Research 1987, 15, 4857 and biotin in the same manner as described in PCT application PCT/US/02198. Fluorescein, biotin and pyrene were also linked in the same manner as reported by Telser, et al . , J. Am. Chem . Soc . 1989, 111 , 6966. A commercial reagent, Amino-Modifier-dT, from Glen Research Corporation (Sterling, VA) can be utilized to introduce pyrimidine nucleotides bearing similar linking groups into oligonucleotides. Sproat, et al . , Nucl . Acids Res . 1987, 15, 4837, have synthesized 5'-mercapto nucleosides and incorporated them into oligonucleotides. Several phosphoramidites and H-phosphonates have been reported for introduction of a 5'-thiol linker via a phosphate linkage (see, Mori, et. al . , Nucleosides and Nucleotides, 1989, 8, 649; WO 89/02931 (Levenson, et al . ) published April 6, 1989; Sinha, et al . , Nucl . Acids . Res . 1988, 16, 2659) . The amidites provide means for attachment of a HS- (CH 2 ) n -0-P(=0) -0-linkage to the oligomer. Also, disulfide- protected mercapto alkanols have been used to yield phosphoramidites (available from Glen Research, Sterling, VA and Clontech, Palo Alto, CA) . The same mercapto alkanols have been attached to controlled pore glass (CPG) to give solid supports which yield 3'-thiolated oligonucleotides having a phosphate or thiophosphate linkage between the linker and the oligonucleotide. In another approach, oligonucleotides having 5'-amino linkers have been converted into oligonucleotides having 5'-thiol linkers by treatment with dithiobis- (N- succinimidyl) propionate or N-succinimidyl-3- (2-pyridyldithio) propionate followed by dithiothreitol (DTT) ( See, Bischoff, et al . , Anal . Biochem . 1987, 164 , 336 and Gaur, et al . , Nucl . Acids Res . 1989, 17, 4404) . Asseline, et al . , Tetrahedron 1992, 48, 1233 and Fidanza, et al . , J. Am. Chem. Soc . 1992, 114 , 5509, have used either the terminal or internucleotide thiosphophate groups to attach pendant groups. Fidanza, et al . , J. Org. Chem. 1992, 57, 2340, have used cystamine (H 2 N-CH 2 - CH 2 -S-S-CH 2 -CH 2 -NH 2 ) to oxidize internucleotide H-phosphonate and provide a -P-NH-CH 2 -CH 2 -SH tether. Zuckerman, et. al . , Nucleic Acids Res . 1987, 15, 5305, have used a 3'-S-alkyl thiol linker in a thymine nucleoside and incorporated the nucleoside into oligonucleotides. Ferentz, et al. , (J. Org. Chem. 1990, 55, 5931 and J " . Am . Chem . Soc . 1991, 113 , 4000) have shown methods of attaching -NH- (CH 2 ) n -SH (n=2,3) at the 4-position of cytosine and the 6-position of adenosine. However, there still remains a need in the art for methods of synthesis for nucleosides and oligonucleosides bearing further thiol-containing species. OBJECTS OF THE INVENTION It is one object of this invention to provide nucleosides, oligonucleotides and oligonucleosides that include alkylthiol chemical functionality. It is a further object of the invention to provide compounds having improved transfer across cellular membranes. It is another object to provide compounds that include intercalators, nucleic acid cleaving agents, cell surface phospholipids, and/or diagnostic agents. It is yet another object to provide improvements in research and diagnostic methods and materials for assaying bodily states in animals, especially disease states. It is an additional object of this invention to provide therapeutic and research materials having improved transfer and up take properties for the treatment of diseases through modulation of the activity of DNA or RNA. BRIEF DESCRIPTION OF THE INVENTION These and other objects are satisfied by the present invention, which provides compounds containing alkylthiol chemical functionality. In one aspect, the invention provides nucleosides having base portions and ribofuranosyl sugar portions. Such nucleosides bear at a 2' -O-position, a 3'-0- position, or a 5' -O-position a substituent having formula: where: R s has formula R A , R A -C(O) -Q-R A , R A -Q-R A -Q-R A ; each R A is independently selected from alkyl having 1 to about 10 carbon atoms; each Q is independently selected from NH, O, and S; R_ is H or a thiol protecting group or has formula S-R 2 , CH 2 C(0) -NH-R 2 , CH 2 -CH=CH-C(0) -R 2 , -CH 2 -CH 2 -NH-S (0) 2 -R 2 , or (maleimido) -R 2 ; and R 2 includes a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter group, an alkylator, an intercalator, a cell receptor binding molecule, a crown ether, a crown amine, a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethylene glycol) . In another aspect, the invention provides oligonucleo¬ tides and oligonucleosides each comprising a plurality of linked nucleosides, wherein each nucleoside includes a ribofuranosyl sugar portion and a base portion and at least one (preferably more than one) of the nucleosides bears at a 2'-0- position, a 3' -O-position, or a 5' -O-position a substituent having formula -R A -S-R X . In yet another aspect, the invention provides nucleosides that bear at a 5-pyrimidine position or at a 2-, 6-, or 8- purine position a substituent having formula -Q-R a -S-Ri, -C=C- R A -Q-C(0)-R A -S-R 1 , -CH=CH-C (0) -Q-R A -S-R 1# or -CH=CH-R A -Q-C(0) -Q- R ft -S-R- L , provided that a 6-purine substituent does not have formula -NH-R A -S-R_ when R x is H or a thiol protecting group. Also provided are oligonucleosides or oligonucleotides containing one or more of such nucleosides. The invention also provides oligonucleotides comprising at least two nucleosides bound by a linkage having formula (5' ) -0-P[X] [Q-R A -S-R X ] -0- (3' ) wherein X is 0 or S, provided that Q is not NH when R_ is H or a thiol protecting group. In another aspect the invention provides methods for preparing oligonucleotides and oligonucleosides comprising the steps of contacting nucleosides according to the invention for a time and under reaction conditions effective to form a covalent bond therebetween. In preferred embodiments, at least one of the nucleosides bears a phosphoramidate group at its 2'- O-position or at its 3' -O-position. In other embodiments, compounds according to the invention are prepared by contacting a nucleoside, oligonucleo- tide or oligonucleoside with derivatizing reagents. For example, a nucleoside, oligonucleotide or oligonucleoside bearing a 2'-hydroxy group, a 3'-hydroxy group, or a 5'-hydroxy group under basic conditions with a 'compound having formula I__- R A -S-R la wherein L α is a leaving group such as a halogen and R la is a thiol protecting group. The present invention also provides methods for inhibiting the expression of particular genes in the cells of an organism, comprising administering to said organism a compound according to the invention. Also provided are methods for inhibiting transcription and/or replication of particular genes or for inducing degradation of particular regions of double stranded DNA in cells of an organism by administering to said organism a compound of the invention. Further provided are methods for killing cells or virus by contacting said cells or virus with a compound of the invention. The compound can be included in a composition that further includes an inert carrier for the compound. DETAILED DESCRIPTION OF THE INVENTION This invention provides nucleosides, oligonucleotides and oligonucleosides containing alkylthiol chemical functionality. The nucleoside subunits can be "natural" or "synthetic" moieties. Each nucleoside is formed from a naturally occurring or synthetic base and a naturally occurring or synthetic pentofuranosyl sugar group. The term "oligonucleotide" refers to a polynucleotide formed from a plurality of linked nucleotide units. The nucleotide units each include a nucleoside unit. In the context of this invention, the term "oligonucleoside" refers to a plurality of nucleoside units that are linked together. In a generic sense, since each nucleotide unit of an oligonucleotide includes a nucleoside therein, the term "oligonucleoside" can be considered to be inclusive of oligonucleotides (i.e., nucleosides linked together via phosphate linking groups) . In a further sense, the term "oligonucleoside" also refers to a plurality of nucleosides that are linked together via linkages other than phosphate linkages. The term "oligonucleoside" thus effectively includes naturally occurring species or synthetic species formed from naturally occurring subunits. For brevity, the term "oligo- nucleoside" will be used to denote both phosphate linked (oligonucleotides) and non-phosphate linked polynucleoside species. Oligonucleosides according to the invention also can include modified subunits. Representative modifications include modification of a heterocyclic base portion of a nucleoside or a sugar portion of a nucleoside. Exemplary modifications are disclosed in the following United States Patent Applications: Serial No. 463,358, filed January 11, 1990, entitled Compositions And Methods For Detecting And Modulating RNA Activity; Serial No. 566,977, filed August 13, 1990, entitled Sugar Modified Oligonucleotides That Detect And Modulate Gene Expression; Serial No. 558,663, filed July 27, 1990, entitled Novel Polyamine Conjugated Oligonucleotides; Serial No. 558,806, filed July 27, 1991, entitled Nuclease Resistant Pyrimidine Modified Oligonucleotides That Detect And Modulate Gene Expression and Serial No. PCT/US91/00243, filed January 11, 1991, entitled Compositions and Methods For Detecting And Modulating RNA Activity. Each of these patent applications are assigned to the assignee of this invention. The disclosure of each is incorporated herein by reference. The term oligonucleoside thus refers to structures that include modified portions, be they modified sugar moieties or modified base moieties, that function similarly to natural bases and natural sugars. Representative modified bases include deaza or aza purines and pyrimidines used in place of natural purine and pyrimidine bases; pyrimidines having substituent groups at the 5 or 6 position; and purines having altered or replacement substituent groups at the 2, 6 or 8 positions. Representative modified sugars include carbocyclic or acyclic sugars, sugars having substituent groups at their 2' position, and sugars having substituents in place of one or more hydrogen atoms of the sugar. Other altered base moieties and altered sugar moieties are disclosed in United States Patent 3,687,808 and PCT application PCT/US89/02323. Altered base moieties or altered sugar moieties also include other modifications consistent with the spirit of this invention. Such oligonucleosides are best described as being structurally distinguishable from yet functionally interchangeable with naturally occurring or synthetic wild type oligonucleotides. All such oligonucleosides are comprehended by this invention so long as they function effectively to mimic the structure of a desired RNA or DNA strand. For use in antisense methodology, the oligonucleosides of the invention preferably comprise from about 10 to about 30 subunits. It is more preferred that such oligonucleosides comprise from about 15 to about 25 subunits. As will be appreciated, a subunit is a base and sugar combination suitably bound to adjacent subunits through, for example, a phosphorous- containing ( e . g. , phosphodiester) linkage or some other linking moiety. The nucleosides need not be linked in any particular manner, so long as they are covalently bound. Exemplary linkages are those between the 3'- and 5' -positions or 2' - and 5' -positions of adjacent nucleosides. Exemplary linking moieties are disclosed in the following references: Beaucage, et al . , Tetrahedron 1992, 48, 2223 and references cited therein; and United States Patent Applications: Serial No. 703,619, filed May 21, 1991; Serial No. 903,160, filed June 24, 1992; Serial No. 039,979, filed March 20, 1993; Serial No. 039,846, filed March 30, 1993; and Serial No. 040,933, filed March 31, 1993. Each of the foregoing patent applications are assigned to the assignee of this invention. The disclosure of each is incorporated herein by reference. It is preferred that the RNA or DNA portion which is to be modulated using oligonucleosides of the invention be preselected to comprise that portion of DNA or RNA which codes for the protein whose formation or activity is to be modulated. The targeting portion of the composition to be employed is, thus, selected to be complementary to the preselected portion of DNA or RNA, that is, to be an antisense oligonucleoside for that portion. Preferred embodiments of this invention include those the compounds of the invention that are complementary to sequences for herpes, papilloma and other viruses. The nucleosides and oligonucleosides of the invention can be used in diagnostics, therapeutics and as research reagents and kits. They can be used in pharmaceutical compositions by including a suitable pharmaceutically acceptable diluent or carrier. They further can be used for treating organisms having a disease characterized by the undesired production of a protein. The organism should be contacted with an oligonucleotide having a sequence that is capable of specifically hybridizing with a strand of nucleic acid coding for the undesirable protein. Treatments of this type can be practiced on a variety of organisms ranging from unicellular prokaryotic and eukaryotic organisms to multicellular eukaryotic organisms. Any organism that utilizes DNA-RNA transcription or RNA-protein translation as a fundamental part of its hereditary, metabolic or cellular control is susceptible to therapeutic and/or prophylactic treatment in accordance with the invention. Seemingly diverse organisms such as bacteria, yeast, protozoa, algae, all plants and all higher animal forms, including warm-blooded animals, can be treated. Further, each cell of multicellular eukaryotes can be treated since they include both DNA-RNA transcription and RNA-protein translation as integral parts of their cellular activity. Many of the organelles ( e . g. , mitochondria and chloroplasts) of eukaryotic cells also include transcription and translation mechanisms. Thus, single cells, cellular populations or organelles can also be included within the definition of organisms that can be treated with therapeutic or diagnostic oligonucleotides. As used herein, therapeutics is meant to include the eradication of a disease state, by killing an organism or by control of erratic or harmful cellular growth or expression. In one aspect, the present invention is directed to nucleosides and oligonucleosides that bear at least one thiol- containing substituent at a ribofuranosyl, pyrimidinyl, and/or purinyl position. Ribofuranosyl substituents preferably have formula -R^S-R^ . and are appended at 2'-0-, 3' -O-, and/or 5'-0- positions. Pyrimidinyl and purinyl substituents preferably have formula -C≡C-R A -Q-C(0) -Ra-S-Ri and are appended at 5- pyrimidine positions and at 2-, 6-, or 8-purine positions. In another aspect, the invention is directed to oligonucleosides containing at least one intemucleoside linkage having formula (5' ) -O-P [X] [Q-R A -S-R -O- (3' ) . Each R A according to the invention is an alkyl moiety independently selected to having 1 to about 10 carbon atoms. The term "alkyl" is intended to include straight chain and branched hydrocarbons. Preferred R A have 1 to about 7 carbon atoms, more preferably 2 to about 6 carbon atoms. R A having formula (CH) n where n = 1-10 are preferred. R_ according to the invention is H, a thiol protecting group (preferably an acid labile protecting group) or has formula S-R 2 , CH 2 C(0) -NH-R 2 , CH 2 -CH=CH-C(O) -R 2 , -CH 2 -CH 2 -NH-S (O) _- R_ , or (maleimido) -R 2 . Numerous thiol protecting groups are known in the art, including, but not limited to, the triphenylmethyl (trityl; Tr) and S-t-butyl, S-p-nitrobenzyl, and S-p-methoxy-benzyl (see; e . g. , Greene and Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley __ Sons, New York, 1991) . Preferred maleimido moieties are those that are N-substituted with R 2 and 3-substituted with S. R 2 can include a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter groups, an alkylator, an intercalator, a cell receptor binding molecule, a crown amine (a "cyclam") , a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethyleneglycol) (PEG; - (CH 2 CH 2 0) 1-200 ) group. That is, R 2 can include a substituent consisting essentially of the foregoing groups. For the purposes of this invention the terms "reporter molecule" and "reporter enzyme" are inclusive of those molecules or enzymes that have physical or chemical properties that allow them to be identified in gels, fluids, whole cellular systems, broken cellular systems and the like utilizing physical properties such as spectroscopy, radioactivity, colorimetric assays, fluorescence, and specific binding. Particularly useful as reporter molecules are biotin and fluorescein dyes. Particularly useful as reporter enzymes are alkaline phosphatase and horseradish peroxidase. Steroids include those chemical compounds that contain a perhydro-1, 2-eye1opentanophenanthrene ring system. Particularly useful as steroid molecules are the bile acids including cholic acid, deoxycholic acid and dehydrocholic acid; steroids including cortisone, digoxigenin, testosterone and cholesterol and even cationic steroids such as cortisone having a trimethylaminomethyl hydrazide group attached via a double bond at the 3 position of the cortisone rings. Proteins and peptides are utilized in their usual sense as polymers of amino acids. Normally peptides comprise such polymers that contain a smaller number of amino acids per unit molecule than do the proteins. Particularly useful as peptides and proteins are sequence-specific peptides and proteins including phosphodiesterase, peroxidase, phosphatase and nuclease proteins. Such peptides and proteins include SV40 peptide, RNaseA, RNase H and Staphylococcal nuclease. Lipophilic molecules include naturally-occurring and synthetic aromatic and non-aromatic moieties such as fatty acids, esters, alcohols and other lipid molecules, cage structures such as adamantane and buckminsterfullerenes, and aromacic hydrocarbons such as benzene, perylene, phenanthrene, anthracene, naphthalene, pyrene, chrysene, and naphthacene. Particularly useful as lipophilic molecules are alicyclic hydrocarbons, saturated and unsaturated fatty acids, waxes, terpenes and polyalicyclic hydrocarbons including adamantane and buckminsterfullerenes. Particularly useful as terpenoids are vitamin A, retinoic acid, retinal and dehydroretinol. Alkylators according to the invention are moieties that can effect attachment of electrophilic groups to targeted molecular structures. Representative alkylators are disclosed by Meyer, et al . , J. Am. Chem. Soc . 1989, 111 , 8517. Intercalators are polycyclic aromatic moieties that can insert between adjacent base pairs without affecting normal Watson-Crick base pairing. Representative intercalators are disclosed by Manoharan in Antisense Research and Applications, Crooke and Lebleu, eds., CRC Press, Boca Raton, 1993. Cell receptor binding molecules according to the invention are vitamins and carbohydrate moieties for which specific receptors exist within a cell . Representative cell receptor binding molecules are disclosed by Application Serial No. PCT/US92/09196, filed October 23, 1992, the contents of which are incorporated herein by reference. Crosslinking agents are moieties that can effect intrastrand or interstrand covalent binding of RNA and/or DNA. Representative crosslinking agents are disclosed in International Patent Application Serial No. PCT/US93/02059, filed March 5, 1993, which is incorporated herein by reference. Useful crown amines are disclosed by Studer, et al . , Helv. Chim. Acta 1986, 69, 2081 and Smith-Jones, et al . , Bioconjugate Chem. 1991, 2, 415. Peptide nucleic acids are disclosed by International Patent Application WO 92/20702, published November 26, 1992. Oligonucleosides according to the invention can be assembled in solution or through solid-phase reactions, for example, on a suitable DNA synthesizer utilizing nucleosides according to the invention and/or standard nucleotide precursors. The nucleosides and nucleotide precursors can already bear alkylthiol groups or can be later modified to bear such groups. In the former case, compounds according to the invention are prepared by, for example, reacting nucleosides bearing at least one free 2'-, 3'-, or 5'-hydroxyl group under basic conditions with a compound having formula L x - (CH 2 ) n -S-R la where I__ is a leaving group and R la is a thiol protecting group. Displacement of the leaving group through nucleophilic attack of an oxygen anion produces the desired thiol derivative. Leaving groups according to the invention include but are not limited to halogen, alkylsulfonyl, substituted alkylsulfonyl, arylsulfonyl, substituted arylsulfonyl, hetercyclcosulfonyl or trichloroacetimidate. A more preferred group includes chloro, fluoro, bromo, iodo, p- (2,4-dinitroanilino)benzenesulfonyl, benzenesulfonyl, methylsulfonyl (mesylate) , p-methylbenzene- sulfonyl (tosylate) , p-bromobenzenesulfonyl, trifluoromethyl- sulfonyl (triflate) , trichloroacetimidate, acyloxy, 2,2,2- trifluoroethanesulfonyl, imidazolesulfonyl, and 2,4,6- trichlorophenyl, with bromo being preferred. Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as amine groups and thiol groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. See, e . g. , Greene and Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley & Sons, New York, 1991. In embodiments wherein thiol-containing functionality is appended to 2'-0-, 3'-0-, or 5'-0- positions, amine functionality in the base portion of the nucleoside preferably next is protected under non-acidic conditions with protecting groups known in the art, including benzoyl and isobutyryl groups. Alternatively, base protection can precede reaction with thiol reagent L_- (CH 2 ) n -S-R la . Suitably protected nucleosides can be assembled into an oligonucleosides according to known techniques. See, e . g. , Beaucage, et al . , Tetrahedron 1992, 48, 2223. Compounds according to the invention also can be prepared by reacting 5-halogen substituted pyrimidine nucleosides or 2- or 8-halogen substituted purine nucleosides with an acetylenic reagent having formula HC=C-CH 2 -Q-R 3 (R 3 = protecting group) under conditions effective to couple the pyrimidine or purine base with the acetylenic reagent and form a nucleoside bearing a substituent having formula -C=C-CH 2 -Q-R 3 at the pyrimidine 5- position or at the purine 2- or 8-position. Numerous suitable protecting groups are known in the art, including, but not limited to: amine protecting groups such as trifluoroacetate (triflate) , allyloxycarbonyl (Alloc) , benzyloxycarbonyl (CBz) , chlorobenzyloxycarbonyl, t-butyloxycarbonyl (Boc) , fluorenylmethoxycarbonyl (Fmoc) , isonicotinyloxycarbonyl (i-Noc) groups; hydroxyl protecting groups such as t- butyldiphenylsilyl, t-butyldimethylsilyl, and dimethoxytrityl groups; and thiol protecting groups such as S-trityl, S-p- methoxybenzylthioether, S-p-nitrobenzylthioether, and S-t- butylthioether. ( see, e . g. , Veber and Hirschmann, et al . , J. Org. Chem. 1977, 42, 3286 and Atherton, et al . , The Peptides, Gross and Meienhofer, Eds, Academic Press; New York, 1983; Vol. 9 pp. 1- 38) . Coupling preferably is mediated by a metal selected from palladium, nickel, platinum and iridium under conditions generally in accordance with Haralambidis, et al . , Nucleic Acids Research 1987, 15, 4857. Once coupling is effected, the protecting group is removed and the resultant free hydroxy, thio, or amino compound is condensed with a suitable thiol derivative having formula R 4 - (CH 2 ) n -S-R la where R 4 is R 5 OOC-, HS, or -NCS where R 5 is H, chloro, alkyl having 1-3 carbon atoms, or active esters of carboxylic acids. Compounds according to the invention also can be prepared by reacting metal-substituted pyrimidine nucleosides or purine nucleosides with an acrylate having formula H 2 C=C-C(0) OR 6 (R 6 = alkyl having 1-3 carbon atoms) under conditions effective to couple the pyrimidine or purine base with the acrylate and form a nucleoside bearing a substituent having formula -CH=CH-C(O)OH at the pyrimidine 5-position or at the purine 2- or 8-position. Coupling is effected under conditions generally in accordance with Dreyer, et al. , Proc. Natl . Acad. Sci . USA 1985, 82, 968. Once coupling is effected, acid is condensed with an amino thiol derivative having formula H 2 N- (CH 2 ) n -S-R la . Compounds according to the invention also can be prepared by reacting nucleosides bearing leaving groups, L 2 , at 5- pyrimidine positions or at 2-, 6-, or 8-purine positions with, for example, aminothiol derivatives having formula HQ-(CH 2 ) n -S- R la under conditions effective to displace the leaving group. Such displacement preferably occurs at room temperature in solvents such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO) . Suitable leaving groups include halogen, alkyl- sulfonyl, substituted alkylsulfonyl, arylsulfonyl, substituted arylsulfonyl, hetercyclcosulfonyl, trichloroacetimidate, and pentafluorophenol. Oligonucleosides according to the invention also can be prepared by assembling an oligonucleoside and appending thiol functionality thereto. For example, oligonucleosides having free hydroxyl groups can be assembled according to known techniques and then reacted with a reagent having formula I__- (CH 2 ) n -S-R la . As will be recognized, however, greater selectivity can be achieved in terms of placement of thiol functionality within an oligonucleoside by introducing such functionality, as discussed above, on selected nucleosides and then using both the selected nucleosides and other nucleosides to construct an oligonucleoside. Thiol functionality also can be appended to phosphonate linkages ( i . e . , (5' ) -O-P (X) (H) -0- (3' ) ) found within an oligonucleoside ( see, e . g. , Todd et al . , J. Chem. Soc . 1966, 239; Frohler et al . , Nucleic Acids Res . 1986, 14 , 160; Letsinger, et al . , Proc . Na tl . Acad. Sci . USA 1989, 86, 6553) For example, oligonucleosides containing at least one phosphonate linkage can be reacted in the presence of base with a thiol reagent having formula HQ- (CH 2 ) n -S-R la under conditions effective form an intemucleoside linkage having formula (5')- 0-P [X] [Q- (CH 2 ) n -S-R la ] -0- (3' ) . Thiol functionality also can be appended to amine- containing linkages (i.e., -CH 2 -NH-0-CH 2 -) found within an oligonucleosides. ( see, e . g. , United States Patent Applications Serial Nos. 039,979 and 039,846, cited above) . For example, oligonucleosides having at least one amine-containing linkage can be condensed a thiol reagent having formula HOC(O) - (CH 2 ) n -S- R la under conditions effective to form an intemucleoside linkage having formula -CH 2 -N[C(O) - (CH 2 ) n -S-R la ] -0-CH 2 - . Once assembled, an oligonucleoside bearing one or more groups having formula -R s -S-R la is treated with acid under conditions to remove protecting group R la . Representative acids include silver cation and mercuric cation. Once deprotected, the oligonucleoside can be contacted with a thiol-containing steroid molecule, reporter molecule, lipophilic molecule, reporter enzyme, peptide, or protein in the presence of a thiol-based coupling reagent. Useful coupling reagents include 2,2' -dithiobis (5-nitropyridine) and other pyridyl disulfides. Alternatively, an oligonucleoside bearing one or more groups having formula -R s -S-H can be contacted with electrophillic moieties having formula (maleimido) -R 2 or L 3 - CH 2 C(0)-R 2 where L 3 is a leaving group. As will be recognized, the sulfur atom on the oligonucleoside bonds with the former electrophillic moiety via 1,4-addition and with the latter via nucleophilic displacement. Preferred electrophillic moieties include phospholipid maleimide, o-phenanthroline-5- iodoacetamide, fluorescein maleimide, and pyrene maleimide (see, e . g. , Example 22) . Thus, the invention first builds the desired linked nucleoside sequence in the normal manner on the DNA synthesizer. One or more (preferably two or more) of the linked nucleosides are then functionalized or derivatized with the lipophilic steroid, reporter molecule, lipophilic molecule, reporter enzyme, peptide or protein. Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. For example, thiol groups in addition to those having formula -R A -S-R., ^ ( e . g. , cysteine, glutathione, penicillamine, 2-pyridylmercaptyl, Br-CH 2 -CO-NH-CH 2 -CH 2 -STr, SH- C- (CH 3 ) 2 CH 2 -NH-CH 2 -CH 2 -NH-CH 2 -C- (CH 3 ) 2 SH, HOOC-CH 2 -CH 2 -S-S-CH 3 OOCS, CH 3 -CO-S-C(CH 3 ) -CH2-C-NH- (CH 2 ) 2 -COOH) can be employed. ( see, e . g. , Dizio, et al . , Bioconjugate Chem. 1991, 2, 353 and Greenfield, et al . , Bioconjugate Chem. 1990, 1, 400) All oligonucleotide sequences are listed in a standard 5' to 3' order from left to right. EXAMPLE 1 S-Trityl-6- ercaptohexylbromide,1,1' ,l"-{{ (6-bromohexyl) thio] ethylidyne] trisbenzene (Compound 1) To a solution of triphenylmethanethiol (Fluka; 69g, 250 mmol) in 500 mL 95% ethanol (EtOH) was added 11 grams of sodium hydroxide dissolved in 75 mL of water (275 mmol) . After stirring for about 15 minutes in argon atmosphere, using an addition funnel, 1, 6-dibromohexane (91.5 g, 375 mmol, 58 mL) dissolved in 100 mL of 95% EtOH was added dropwise over a period of 1 hour with vigorous stirring. After about 15 minutes of stirring of addition, a brown white solid separates out from the reaction flask. After stirring for additional 4 hours, the reaction mixture was filtered. The filtrate was evaporated under high vacuum and the oily residue was combined with the filtered residue and dissolved in 500mL CH 2 C1 2 , filtered again, the filtrate was washed once with water (200 mL) and once with saturated NaCl solution. After drying the CH 2 C1 2 layer over MgS0 4 , it was concentrated to 200 mL in volume. About 200 mL of hexane was added and the solution was left in freezer. Three crops of cream white product was isolated out. Total yield 81g (184 mmol, 73% yield) . After one more recrystallization the product melted at 91-92°C. Portions of the product are independently treated with sodium cyanide followed by hydrolysis to give the corresponding acid, S-trityl-6-mercaptohexanoic acid (Compound 2) , with lithium azide followed by triphenylphosphine reduction to give the corresponding amine, S-trityl-6-mercapto hexylamine (Compound 3) , and with sodium hydrogen sulfide to give the correspondingthiol, (1-S-trityl-thio-hexylmercaptan) (Compound 4) . EXAMPLE 2 2' -O- [6- [ (Triphenylmethyl) thio]hexyl] -adenosine and 3' -O- [6- [ (triphenylmethyl) thio] exyl] -adenosine (Compounds 5 and 6) . Adenosine (22.5g) was alkylated with this S-trityl-6- mercaptohexylbromide (37.5g) in the presence of DMF and sodium hydride to yield a 2'- 0- (Compound 6) and 3' -O-alkylated (Compound 5) mixture in the ratio of 84:16 (as judged by 13 C NMR) . The yield was 27%. EXAMPLE 3 N- Benzoyl - 2 ' -0- [6- [ (triphenylmethyl) thio] hexyl] -adenosine ( Compound 8 ) and W- benz oyl - 3 ' - O - [ 6 - t (triphenylmethyl) thio] exyl] -adenosine (Compound 7). To 16.5 grams of alkylation mixture (5 and 6, 26.4 mmols) in 260 mL of dry pyridine added 17 mL of chlorotrimethyl silane with external cooling with ice bath and stirring. After 30 minutes, 15.6 mL of benzoyl chloride (134.3 mmols) was added and the ice bath was removed. After 2 hours the reaction mixture was again cooled in an ice bath and 55 L of ice-cold water was added. After 15 minutes of stirring, 55 mL of cone. NH 4 OH was added. After an additional 30 minutes the reaction mixture was evaporated to an oil on a rotoevaporator and dissolved in 300 mL CH 2 C1 2 and extracted with saturated NaHC0 3 solution (2 x 100 mL) . The organic layer was dried and loaded into a silica gel (750 grams) and eluted with 7:3 ethyl acetate:hexane to give 18.3g (25.10 mmol) of benzoylated 2' and 3' isomeric mixture (Compounds 7 and 8) 95.1% yield. EXAMPLE 4 ff-Benzoyl - 5 ' - O - [Dimethoxytri tyl] - 2 ' - O - [ 6 - [ (triphenylmethyl) thio]hex yl] -adenosine (Compound 10) and N- Benz oyl - 5 ' - O - [Dime thoxytri tyl ] - 3 ' - O - [ 6 - [ (triphenylmethyl) thio]hexyl] -adenosine (Compound 9) . The base protected nucleoside mixture from the previous step was coevaporated with 2x100 mL of anhydrous pyridine. The resultant material was redissolved in 100 mL of anhydrous pyridine and with stirring, 13.9g (41.0 mmol) dimethoxytritylchloride was added. The reaction mixture was stirred for 1.5 hours, after which thin layer chromatography (TLC; hexane:ethyl acetate (EtOAc) , 1:1) showed disappearance of starting material. Methanol (20 mL) was added and the reaction was stirred for 30 minutes. Pyridine was evaporated and the residue was coevaporated once with 200 mL of toluene. The resultant residue was dissolved in 100 mL of CH 2 C1 2 and applied to a silica gel column (lOOOg, packed in hexane) . The column was eluted with the following solvents: 100% Hexane (1L) ; 45:55 EtOAc-hexane (3L) 50 :50 EtOAc-hexane (3L) and 55:45 EtOAc-hexane until all 2'-0-isomer was eluted out. Then it was eluted with 60:40 EtOAc:Hexane 2 liter followed by 70:30 EtOAc:Hexane until all 3'-0-isomer is off the column. The isolated yields (56% combined yield) were: 10.3g [2'-isomer (Compound 10)] ; 2.4g (3'-isomer) (Compound 9) and 1.9g (2' + 3' isomeric mixture) . R f = 0.28 for 2'-isomer in hexane:EtOAc 1:1 and R f = 0.13 for 3'-isomer (Compound 9) in the same solvent system. EXAMPLE 5 Adenosine-N-benzoyl-5' -0- [bis(4-methoxyphenyl-O-phenylmethyl] - 2" -O- [6- [ (triphenylmethyl) thio]hexyl] -, 3' - [2-cyanoethyl bis (1-methyle hyl)phosphoramidite] The nucleoside N-benzoyl-5' -O- [Dimethoxytrityl] -2'-0- [6- [(triphenylmethyl) thio] hexyl] -adenosine (Compound 10; 4.6 g, 4.46 mMol) was dissolved in 60 mL CH 2 C1 2 anhydrous. Diisopropylamine tetrazolide salt (0.4g, 2.23 mmol) was added followed by phosphitylation reagent. The reaction mixture was stirred overnight. TLC analysis (1:1 EtOAc:Hexane) showed completion (>95%) of the reaction. Then the mixture was transferred into 100 mL of saturated ΝaHC0 3 in a separatory funnel. The reaction was washed with 100 mL CH 2 C1 2 containing 1% Et 3 N. The organic layer was washed with 100 mL of saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated to give 6.75 g of the crude product. It was then purified in a silica column (200 g, in a 25 cm x 7.5 cm column) packed in 50:50 EtOAc:hexane containing 0.1% Et 3 N. The column was eluted with the same solvent followed by 60:40 EtOAc: hexane to give the product 11 as a colorless foam. (4.38 g, 3.6 mmol, 81% yield) . 31 P NMR (CDC1 3 ) : 150.6, 151.4 ppm (d) . EXAMPLE 6 Controlled Pore Glass (CPG) Attached To Nucleoside 10 (Compound 17) . Succinylated CPG, prepared according to Damha, et al . , Nucleic Acids Res . 1990, 18, 3813, (0.3 g, with a loading of approximately 80 micromoles/g, dried under vacuum for 3 hours immediately before use) was added to 3 ml anhydrous pyridine in a 50 ml round-bottom flask. 1- (3-Dimethylaminopropyl) -3-ethyl carbo-diimide (0.12 g, 0.63 mmol), triethyla ine (25 ml, distilled over CaH 2 ) , dimethylaminopryidine (0.005 g, 0.03 mmol) and nucleoside 10 (0.21 g, 0.203 mmol) were added under Ar and the mixture shaken mechanically for 19 hours. More nucleoside (0.025 g, 0.025 mmol) was added and the mixture shaken an additional 5.5 hours Pentachlorophenol (0.045 g, 0.17 mmol) was added and the mixture shaken 18 hours. CPG was filtered off and washed successively with dichloromethane, triethylamine, and dichloromethane. CPG was then dried under vacuum, suspended in 15 ml piperidine and shaken 30 min. The product, nucleoside-CPG (Compound 17) , was filtered off, washed thoroughly with dichloromethane and again dried under vacuum. Extent of loading (determined by spectrophotometric assay of dimethoxytrityl cation in 0.3 M p-toluenesulfonic acid at 498 nm) was approximately 30 mmol/g. EXAMPLE 7 Isolation Of Compounds 7 and 8 Compound 10 (0.50 g, 0.48 mmol) was dissolved in dichloromethane. Acetic acid (80%) in water was added and the mixture stirred overnight. The solvents were evaporated in vacuo and the residue dissolved in dichloromethane and loaded onto a silica gel column. The resultant product 8 (290 mg, 83% yield, R f =0.38 in 80% ethyl acetate in hexanes) was eluted with a gradient of 50% to 100% ethyl acetate in hexanes. Product was analyzed by 1 H, 13 C, and 13 C-APT NMR and mass spectroscopy. The corresponding 3'-isomer 9 was similarly deprotected and purified to yield the 5' -deprotected product 7 (220 mg, 63%, R f =0.51) . Product was analyzed by NMR and mass spectroscopy. EXAMPLE 8 Isolation Of Compounds 5 and 6 Nucleoside 8 (200 mg, 0.27 mmol) was dissolved in 10 mL pyridine in a 500 mL pressure flask. Fresh ammonium hydroxide (125 mL) was added and the reaction mixture was heated at 55° in a water bath. After 3 days the mixture was cooled to 0°, transferred to a 500 mL round-bottom flask and the solvents removed in vacuo. The residue was dissolved in dichloromethane, extracted once with saturated NaHC0 3 and saturated NaCl and dried over MgS0 4 . Solvent was removed in vacuo, the residue redissolved in a small amount of dichloromethane and applied to a silica gel column. Compound 6 (150 mg, 89%, R f =0.50 in 100% ethyl acetate) was eluted with a gradient of 50% to 100% ethyl acetate in hexanes followed by 20% MeOH in ethyl acetate. The corresponding 3'-isomer 7 was similarly deprotected and purified to yield product 5 (125 mg, 87% yield, R f =0.43) . EXAMPLE 9 2 ' -o- [6-Thio hexyl] -adenosine (Compound 18) and 3 # -0-[6-Thio hexyl] -adenosine (Compound 19) Nucleoside 6 (130 mg, 0.19 mmol) is dissolved in 4 mL chloroform. Silver Nitrate (8 mM) in EtOH (12 mL) is added and the reaction mixture stirred for 45 minutes. Dithiothreitol (0.35 M) in chloroform (3 mL) is added and the reaction stirred overnight. The white precipitate is filtered off and the solvent removed in vacuo . The residue is dissolved in dichloromethane, extracted once with saturated NaHC0 3 and saturated NaCl and dried over MgS0 4 . The solvent is removed in vacuo . The product is purified on a silica gel column or by HPLC. The product (Compound 18) is analyzed by 1 H, 13 C, and 13 C- APT NMR and mass spectroscopy. Similarly, nucleoside 5 (95 mg, 0.15 mmol) is deprotected and the product 19 purified and analyzed. EXAMPLE 10 Attachment Of Thiol Linker At 5-Position Of Pyrimidines A. 3' , 5' -di-toluyl-5-iododeoxyuridine is condensed with N-trifluoroacetyl-propargylamine in the presence of bis- (triphenylphosphine) palladium chloride and cuprous iodine (Haralambidis, et al . , Nucleic Acids Res . 1987, 15, 4857) . This nucleoside is then deprotected to give the free amine at 5 position which is condensed with HOOC- (CH 2 ) 6-S-Tr, (Compound 2) . B. Preparation of 2' -deoxyuridine-5- (propionic acid methyl ester) is carried out according to the published procedure of Telser et al . , J. Am. Chem. Soc. 1989, 111 , 6966. Briefly, 5-chloro-mercury-2' -deoxyuridine is reacted with methyl acrylate under the conditions described by Dreyer, et al . , Proc. Natl . Acad. Sci . USA 1985, 82, 968. The resultant 2' -deoxyuridine-5- (propenoic acid methyl ester) is reduced with hydrogen/palladium on carbon to yield 2'- deoxy uridine-5- (propionic acid methyl ester) . This compound is converted to the 5' -dimethoxytrityl derivative and then reacted with l-S-trityl-hexyl-6-amine 3 by an ester-amide exchange reaction as described by Dreyer, et al . for other amines. EXAMPLE 11 Attachment Of Thiol Linker At 2-Position Of Purines. 2-Fluoro-2' -deoxyinosine is reacted with compound 3 following the conditions of Harris, et al . , J. Am. Chem. Soc. 1991, 113 , 4328. The resulting 2-position thiol linker placed nucleoside is further derivatized and incorporated into oligonucleotides. EXAMPLE 12 Attachment Of Thiol Linker At 8-Position Of Purines. 8-Bromoadenosine is reacted with the sodium salt of HS- (CH2) 6 -STr. (Compound 4) . The resulting 8-position modified nucleoside is then further modified and incorporated into oligonucleotides. EXAMPLE 13 Preparation Of A Phosphonate Internucleotide Linkage And Attachment Of A Thiol Linker Thereto. A fully protected oligonucleotide with an internucleotide H-phosphonate at a specific site synthesized following the protocol of Froehler, et al . , Nucleic Acids Research 1986, 14 , 160. This compound is oxidized with compound 4 in carbon tetrachloride-triethylamine medium to give the phosphorothioate triester 0=P-S- (CH2) 6 -STr. The oligonucleotide residue is further utilized for the full length oligonucleotide synthesis. The resultant oligonucleotide has the thiol linker attached to the backbone. EXAMPLE 14 Preparation Of An Amine-containing Backbone And Attachment Of A Thiol Linker Thereto. A dinucleoside protected dimer with either an 3'-CH 2 - NH-0-CH 2 -5' or 5'-CH 2 -NH-0-CH 2 -3' linkage is synthesized by the procedure of Vasseur, et al . , J. Am. Chem. Soc . 1992, 114 , 4006. This dimer is coupled with compound 2 using EDC and N-hydroxy succinimide. The coupled product has the configuration Tr-S- (CH2) 6-CO-N- . The dimer is then 5'- dimethoxytritylated and 3' -phosphitylated and incorporated into full-length oligonucleotide synthesis. EXAMPLE 15 Conversion Of Thiol 2'-0-hexyl Nucleoside Into Cholesterol Amidite Nucleoside 10 (2g) was dissolved in 40 mL of CHC1 3 containing 1 mL of triethylamine and treated with 8 mmol ethanolic silver nitrate (120 mL) at room temperature during which period the solution becomes turbid from clear. TLC (ethyl acetate:hexane 50:50) indicated a faster moving compound than the starting material and trityl on the top of the chromatograph. At this time 0.35 M solution of DTT in 40 mL of CHC1 3 was added and the resultant gelatinous precipitate was filtered over celite. The solution was dried and evaporated. The final TLC showed a slower moving spot than the starting material as expected out of a free thiol compound. It was used in the next* step without any future purification. 2, 2' -Dithiobis (5-nitropyridine) is treated with the thiol nucleoside in methylene chloride overnight . The precipitated 5-nitro pyridine-2-thione is removed by filtration, and the filtrate is concentrated. The resultant product 14 is treated with thiocholesterol in CH 2 C1 2 and shaken overnight to give the disulfide compound with the cholesterol . The cholesterol nucleoside is phosphitylated (compound 15) and used in oligonucleotide synthesis. EXAMPLE 16 Conversion Of The Thiol Linker With A Trityl Protecting Group Into A Thiol Linker Protect By Disulfide Linkage. Compound 14 is treated with propylmercaptan in CH 2 C1 2 and stirred overnight. The resulting disulfide compound (with - (CH 2 ) 6 -S-S-CH 2 -CH 2 -CH 3 linkage) is further derivatized and incorporated into oligonucleotides. The free thiol group is liberated, before conjugation, by the addition of DTT. EXAMPLE 17 Conversion To A Base Labile Thiol linker. The free nucleoside in the previous step (Compound 14) is treated with CBzCl (carbobenzyloxy chloride) in triethylamine. The thiol group is protected as a carbobenzyloxy ester group and phosphitylated and incorporated into oligonucleotides. Ammonia treatment for deprotection followed by DTT treatment yielded a free thiol containing oligonucleotide. EXAMPLE 18 Oligonucleotide Synthesis. A 0.15 M solution of modified amidite (Compound 11) in anhydrous CH 3 CN was used in a 38OB ABI DNA synthesizer to synthesize the following oligonucleotides: d(GAA*CT) P=0 (SEQ ID N0:1) d(GAA*CT) P=S (SEQ ID NO:2) wherein "*" denotes the thiol-modified nucleoside. Oligonucleotides with normal P=0 backbones and modified P=S backbones were synthesized. The oligonucleotides containing P=S backbones were synthesized using the Beaucage reagent and standard synthesis cycles. During the phosphodiester synthesis, oxidation of the tervalent phosphorous was achieved using a 0.5 M solution of _fc-BuOOH in CH 3 CN since the tritylthioether group was sensitive to iodine/water solution. A coupling efficiency of greater than 90% was observed during the modified amidite coupling. For example, a 1 mmol synthesis of SEQ ID NO:l yielded 36 OD units of purified oligonucleotide (72% overall isolated yield) . Both P=0 and P=S oligonucleotides were dimethoxytrityl-on purified and the dimethoxytrityl group was removed with 15% acetic acid and then purified again. NMR analysis of SEQ ID N0:1 and SEQ ID NO:2 showed the integrity of these compounds. For SEQ ID NO:l, the trityl group resonance is observed between 7.0 and 7.5 ppm, and 31 P showed the expected 4 peaks. It is noteworthy that one of the signals is shifted about 0.5 ppm from the other signals, as observed in other RNA/DNA hybrids. In the case of the phosphorothioate SEQ ID NO:2 a total of 64 signals is expected due to diastereomeric nature of chiral phosphorothioates; the multiplicity observed illustrates this fact. SEQ ID NO:l was digested to individual nucleosides with snake venom phosphodiesterase and calf-intestinal alkaline phosphatase in order to confirm its nucleoside composition. Some resistance to enzymatic digestion (nuclease resistance) compared to unmodified oligonucleotides was observed which may be due to the presence of the 2 ' - O- tether. Using the same amidite, the following antisense oligonucleotide sequences also were made: TGGGA*GCCATAGCGAGCC P=S (SEQ ID NO:3), ICAM antisense oligonucleotide with P=S backbone; TCTGAGTAGCAGAGGAGCTA*AG P=0 (SEQ ID NO:4) , sequence in the 5' -cap region of ICAM with P=0 backbone. SEQ ID NO:3 serves to evaluate the tritylthioether group in uptake experiments to determine its ability to inhibit ICAM (Intra Cellular Adhesion Molecules) protein expression. SEQ ID NO:4 is conjugated to O-phenanthroline and targeted against the 5' -cap-messenger RNA of ICAM system to cleave the target RNA. EXAMPLE 19 Conjugation Reactions Of 2' -O-hexylthiol Linker To illustrate the conjugation potential of the 2 ' - O- thiol tether, SEQ ID NO:l was treated with 0.1M AgN0 3 in TEAA buffer followed by DTT treatment to generate a free thiol group. At this stage, it was reacted with four classes of compounds each having an either haloacetamide or a maleimide group and the desired functionality at the other end. The following compounds were employed: (1) a phospholipid maleimide, which can offer cell signalling and trafficking properties to nucleic acids; (2) 5-iodoacetamido-O- phenanthroline, which is a nucleic acid cleaving agent; this particular conjugation offers an added advantage of optimal placement for the cleaving agent as this reagent when complexed to cuprous ion reacts via a minor groove attack at the C-l' position; (3) pyrenemaleimide, which may stabilize the nucleic acid duplex via intercalation; and (4) fluorescein maleimide, which is used as a general diagnostic tool, serving to follow the uptake of antisense oligonucleotides. The conjugations were carried out in phosphate buffer (pH 8.0) and yields were greater than 95% (no starting oligonucleotide was apparent in the HPLC analysis) . The conjugates were easily purified by size exclusion and reverse phase HPLC and characterized by their UV-VIS spectra (where applicable) . The retention times of different oligonucleotides and their conjugates are given in Table I. Fluorescein maleimide, pyrene maleimide and phospholipid maleimide were purchased from Molecular Probes (Eugene, Oregon) . O-Phenanthroline-5-iodoacetamide was synthesized according to the published procedure of Sigman, Biochemistry 1990, 29, 9097. Table I HPLC retention times of SEQ ID NO: 1 and SEQ ID NO:2 and their derivatives a A normal diester for comparison with entry 3. HPLC conditions: C-18 column; linear 1% increase of CH 3 CN concentration for every minute. EXAMPLE 20 5'-O- (S-Trityl-hexylthio)thymidine (Compound 20) 5' -Dimethoxytrityl thymidine is treated with 2 equivalents of benzyloxymethyl chloride in methylene chloride in the presence of excess of diisopropylethylamine. N-3,3'- O-di-benzyloxymethyl protected nucleoside is obtained and purified by silica column. 5'-Dimethoxytrityl group is then removed by treatment with 80% acetic acid and the product is treated with NaH in THF followed by adding compound 1. 5' - Alkylated compound is obtained and on hydrogenolysis the benzyloxymethyl groups are removed. The compound is then phosphitylated and used to synthesize oligonucleotides having a 5' -thiol linker built in the nucleoside. EXAMPLE 21 Synthesis Of 3' -thiol Terminal Oligonucleotide Via 2'-0-(S- trityl Hexyl Mercaptan Linker) And 3 ' -O- (S-trityl-hexyl- mercaptan) Linker Compound 17 is used to synthesize an oligonucleotide with the following sequence, GCATA*, where modified adenosine is directly attached to CPG. The resultant oligonucleotide has a nucleotide with a thiol tether 2' -O- (CH2) 5-S-Tr group at the 3'-end of the oligonucleotide. Similarly, nucleoside 9 was attached to Control Pore Glass according to Example 6 and used for oligonucleotide synthesis. The product oligonucleotide has a nucleotide at the 3' terminal which has a 3' -0- (CH2) 6-S-Tr group. EXAMPLE 22 A. Determination Of Cellular Uptake And Activity Of Thiol Linker Containing Oligonucleotide. This is determined by the inhibition of ICAM-1 utilizing the method of Chiang, et al . , J. Biol . Chem. 1991, 266 18162. ICAM-1 Assay: ICAM-1 expression on the cell surface was determined by ELISA using cells grown to confluence in 96-well plates. Cells were washed three times with Dulbecco's phosphate-buffered saline and fixed for 20 minutes in 2% formaldehyde diluted in Dulbecco's PBS. The cells were washed three times with Dulbecco's PBS, blocked for 1 hour at 37°C with 2% bovine serum albumin in Dulbecco's PBS, and incubated with ICAM-1 monoclonal antibody 84H10 (0.5 μg/ml) for 1 hour at 37°C. Antibody bound to the cells was determined by incubation with a 1:1000 dilution of biotinylated goat anti-mouse IgG followed by incubation with a 1:1000 dilution of B-galactosidase- conjugated streptavidin. The plates were developed with 100 μl of 3.3 mM chlorophenolred-B-D-galactopyranoside in 50 mM sodium phosphate, 1.5 mM MgC12, pH 7.0. Product formed was detected by absorbance at 575 nm. The data were expressed as percent control activity, which was calculated as described by Chiang, et al . , in the above reference. Oligonucleotide Treatment of Cells: Cells were washed three times with pti-MEM prewarmed to 37°C. Opti-MEM containing either 10 μg/ml DOTMA solution (HUVEC) or 20 mg/ml DOTMA solution (A549 eels) was added to each well of the plate (100 μl) . Oligonucleotides were sterilized by centrifugation through 0.2 μM Centrex cellulose acetate filters. Oligonucleotides were added as 20 X stock solution to the wells and incubated for 4 hours at 37°C and then stimulated with the appropriate cytokine for 14-16 hours as indicated. ICAM-1 expression was determined as described above. SEQ ID NO:3 is used in the above assay to assess its effect on ICAM expression. It is seen that the oligonucleotide effectively inhibits ICAM protein synthesis. B. RNA Cleavage Assay Using Oligonucleotide Containing Thiol Linker. SEQ ID NO:4 is thiol deprotected and conjugated to O- phenanthroline reagent. The conjugate is targeted against 5' -capped RNA of the ICAM system. The hybrid is incubated at 37°C over a 48 hour period in the presence of excess Cu(II) salt under buffered conditions. Analysis of the reaction by gel electrophoresis (as described by Baker, J " . Am. Chem. Soc . 1993, 115, 3378) demonstrate that the oligonucleotide-O- phenanthroline-Cu complex cleave the target RNA strand. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANTS: ISIS Pharmaceuticals, Inc. (ii) TITLE OF INVENTION: Thiol-Derivatized Nucleosides And Oligonucleosides (iii) NUMBER OF SEQUENCES: 4 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Woodcock Washburn Kurtz Mackiewicz and Norris (B) STREET: One Liberty Place - 46th Floor (C) CITY: Philadelphia (D) STATE: PA (E) COUNTRY: U.S.A. (F) ZIP: 19103 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 08/116,801 (B) FILING DATE: 03-SEP-1993 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Joseph Lucci (B) REGISTRATION NUMBER: 33,307 (C) REFERENCE/DOCKET NUMBER: ISIS-1670 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 215-568-3100 (B) TELEFAX: 215-568-3439 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) ( ix) FEATURE : (A) NAME/KEY : τnisc_f eature (B) LOCATION : 3 (D) OTHER INFORMATION: /note= "2' -O-thiol modified-2' -deoxyadenosine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: GAACT 5 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 3 (D) OTHER INFORMATION: /note= "2' -0-thiol modified-2' -deoxyadenosine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2 : GAACT ! (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 5 (D) OTHER INFORMATION: /note= "2' -O-thiol modified-2' -deoxyadenosine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TGGGAGCCAT AGCGAGCC 18 (2) INFORMATION FOR SEQ ID NO:4 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 19 (D) OTHER INFORMATION: /note= "2' -O-thiol modified-2' -deoxyadenosine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2 : TCTGAGTAGCA GAGGAGCTAA G 21

Claims: WHAT IS CLAIMED IS: 1. A compound comprising a plurality of linked nucleosides, wherein: each nucleoside includes a ribofuranosyl sugar portion and a base portion; and at least one of said nucleosides bears at a 2'-0- position, a 3' -O-position, or a 5' -O-position a substituent having formula: where: R s has formula R A , R A -C(0) -Q-R A , R A -Q-R A -Q-R A ; each R A is independently selected from alkyl having from 1 to about 10 carbon atoms; each Q is independently selected from NH, O, and S; R_ is H or a thiol protecting group or has formula S-R 2 , CH 2 C (O) -NH-R 2 , CH 2 -CH=CH-C(0) -R 2 , -CH 2 - CH 2 -NH-S (0) 2 -R 2 , or (maleimido) -R 2 ; and R 2 includes a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter group, an alkylator, an intercalator, a cell receptor binding molecule, a crown ether, a crown amine, a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethylene glycol) . 2. The compound of claim 1 wherein more than one of said nucleosides bears said substituent at a 2'-0- position, a 3' -O-position, or a 5' -O-position. 3. The compound of claim 1 wherein R A is (CH 2 ) n where n is an integer from 1 to about 10. 4. The compound of claim 3 wherein n is 6. 5. The compound of claim 1 wherein R_ is H or trityl 6. The compound of claim 1 wherein R_ is S-R 2 and R 2 is thiocholesterol, 7. The compound of claim 1 wherein R_ is CH 2 C(0)- NH-R 2 and R 2 is o-phenanthroline. 8. The compound of claim 1 wherein R_ is phospholipid maleimido, fluorescein maleimido, or pyrene maleimido. 9. A nucleoside comprising a ribofuranosyl sugar portion and a base portion, wherein said nucleoside bears at a 2' -O-position, a 3' -O-position, or a 5' -O-position a substituent having formula: where: R s has formula R A , R A -C(O) -Q-R A , R A -Q-R A -Q-R A ; each R A is independently selected from alkyl having from 1 to about 10 carbon atoms; each Q is independently selected from NH, O, and S; R_ is H or a thiol protecting group or has formula S-R 2 , CH 2 C (0) -NH-R 2 , CH 2 -CH=CH-C(0) -R 2 , -CH 2 - CH 2 -NH-S (0) 2 -R 2 , or (maleimido) -R 2 ; and R 2 includes a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter group, an alkylator, an intercalator, a cell receptor binding molecule, a crown ether, a crown amine, a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethylene glycol) . 10. The compound of claim 9 wherein R A is (CH 2 ) n where n is an integer from 1 to about 10. 11. The compound of claim 10 wherein n is 6. 12. The compound of claim 9 wherein R_ is H or trityl. 13. The compound of claim 9 wherein R_ is S-R 2 and R 2 is thiocholesterol 14. The compound of claim 9 wherein R_ is CH 2 C(0)- NH-R 2 and R 2 is o-phenanthroline. 15. The compound of claim 9 wherein R_ is phospholipid maleimido, fluorescein maleimido, or pyrene maleimido. 16. A compound comprising a plurality of linked nucleosides, wherein: each nucleoside includes a ribofuranosyl sugar portion and a base portion; and at least one of said 'nucleosides bears at a 5- pyrimidine position or at a 2-, 6-, or 8-purine position a substituent having formula: -Q-R A -S-R lf - or -C≡C-R A -Q-C(0) -R A -S-R ι; -CH=CH-C(0) -Q-R A -S-R ι; or -CH=CH-R A -Q-C(0) -Q-R A -S-R ι; where: each R A is independently alkyl having from 1 to about 10 carbon atoms; Q is NH, 0, or S; R_ is H or a thiol protecting group or has formula S-R 2 , CH 2 C(0) -NH-R 2 , CH 2 -CH=CH-C(O) -R 2 , -CH 2 - CH 2 -NH-S (0) 2 -R 2 , or (maleimido) -R 2 ; and R 2 includes a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter group, an alkylator, an intercalator, a cell receptor binding molecule, a crown ether, a crown amine, a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethylene glycol) ; provided that a 6-purine substituent does not have formula - H-Ra-S-R j. when R x is H or a thiol protecting group. 17. The compound of claim 16 wherein more than one of said nucleosides bears said substituent at a 5- pyrimidine position or at a 2-, 6-, or 8-purine position. 18. The compound of claim 16 wherein R A is (CH 2 ) n where n is an integer from 1 to about 10. 19. The compound of claim 18 wherein n is 6. 20. The compound of claim 16 wherein R_ is H or trityl. 21. The compound of claim 18 wherein said nucleoside bears at a 5-pyrimidine position a substituent having formula -C=C-CH 2 -NH-C(0) - (CH 2 ) n -S-R 1 . 22. The compound of claim 18 wherein said nucleoside bears at a 5-pyrimidine position a substituent having formula -CH=CH-C(0) -NH- (CH 2 ) n -S-R 1 . 23. The compound of claim 18 wherein said nucleoside bears at a 2- or 8-purine position a substituent having formula -NH- (CH 2 ) n -S-R 1 . 24. A nucleoside comprising a ribofuranosyl sugar portion and a base portion, wherein said nucleoside bears at a 5-pyrimidine position or at a 2-, 6-, or 8-purine position a substituent having formula: -Q-R A -S-R ι; or -C=C-R A -Q-C(0) -R A -S-R ι; -CH=CH-C(0) -Q-R A -S-R ι; or -CH=CH-R A -Q-C(0) -Q-R A -S-R**.; where: each R A is independently alkyl having from 1 to about 10 carbon atoms; Q is NH, 0, or S; R_ is H or a thiol protecting group or has formula S-R 2 , CH 2 C(0) -NH-R 2 , CH 2 -CH=CH-C(0) -R 2 , -CH 2 - CH 2 -NH-S (0) 2 -R 2 , or (maleimido) -R 2 ; and R 2 includes a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter group, an alkylator, an intercalator, a cell receptor binding molecule, a crown ether, a crown amine, a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethylene glycol) ; provided that a 6-purine substituent does not have formula -NH-R A -S-R- L when R_ is H or a thiol protecting group. 25. The compound of claim 24 wherein R A is (CH 2 ) n where n is an integer from 1 to about 10. 26. The compound of claim 25 wherein n is 6. 27. The compound of claim 24 wherein R_ is H or trityl. 28. The compound of claim 25 wherein said nucleoside bears at a 5-pyrimidine position a substituent having formula -C≡C-CH 2 -NH-C(O) - (CH 2 ) n -S-R^ 29. The compound of claim 25 wherein said nucleoside bears at a 5-pyrimidine position a substituent having formula -CH=CH-C(O) -NH- (CH 2 ) n -S-R^ 30. The compound of claim 25 wherein said nucleoside bears at a 2- or 8-purine position a substituent having formula -NH- (CH^-S-R- L . 31. The compound of claim 25 wherein said nucleoside bears at a 2-, 6-, or 8-purine position a substituent having formula -S- (CH 2 ) n -S-R 1 . 32. A compound comprising a plurality of linked nucleosides, wherein: each nucleoside includes a ribofuranosyl sugar portion and a base portion; and at least two of said nucleosides are bound by a linkage having formula: (5')-0-P[X] [Q-R Λ -S-R -O- O') where: X is 0 or S; Q is NH, 0, or S; R A is alkyl having from 1 to about 10 carbon atoms; R_ is H or a thiol protecting group or has formula S-R 2 , CH 2 C(0) -NH-R 2 , CH 2 -CH=CH-C(0) -R 2 , -CH 2 - CH 2 -NH-S (0) 2 -R 2 , or (maleimido) -R 2 ; and R 2 includes a steroid molecule, a reporter molecule, a lipophilic molecule, a reporter enzyme, a peptide, a protein, a reporter group, an alkylator, an intercalator, a cell receptor binding molecule, a crown ether, a crown amine, a porphyrin, a crosslinking agent, a peptide nucleic acid, or a thiol attached to a poly(ethylene .glycol) ; provided that Q is not NH when R_ is H or a thiol protecting group. 33. The compound of claim 32 wherein R A is (CH 2 ) n where n is an integer from 1 to about 10. 34. The compound of claim 33 wherein n is 6. 35. The compound of claim 32 wherein R_ is H or trityl . 36. The compound of claim 33 wherein said nucleosides are bound by a linkage having formula -0-CH 2 - P[0] [S-(CH 2 ) n -S-R 1 ]-0-. 37. A compound having formula: where: L x is a leaving group; R A is alkyl having 1 to about 10 carbon atoms; and R la is an acid labile thiol protecting group. 38. The compound of claim 37 having formula Br- (CH 2 ) n -R la . 39. A process for derivatizing a nucleoside or oligonucleoside bearing a 2'-hydroxy group, a 3'-hydroxy group, or a 5'-hydroxy group, comprising contacting said nucleoside or oligonucleoside with a compound having formula L^R^S-R^ for a time and under conditions effective to form a linkage having formula -0-R A -S-R la , wherein 1__ is a leaving group and R la is an acid labile thiol protecting group. 40. The process of claim 39 further comprising contacting said linkage with acid to remove said protecting group. 41. A method for modulating the production of a protein by an organism comprising contacting an organism with a compound of claim 1. 42. A method for modulating the production of a protein by an organism comprising contacting an organism with a compound of claim 9. 43. A method for modulating the production of a protein by an organism comprising contacting an organism with a compound of claim 16. 44. A method for modulating the production of a protein by an organism comprising contacting an organism with a compound of claim 24. 45. A method for modulating the production of a protein by an organism comprising contacting an organism with a compound of claim 32. 46. A method for modulating the production of a protein by an organism comprising contacting an organism with a compound of claim 37. 47. A method of treating an animal having a disease characterized by undesired production of protein comprising contacting said animal with a compound of claim 1. 48. A method of treating an animal having a disease characterized by undesired production of protein comprising contacting said animal with a compound of claim 9. 49. A method of treating an animal having a disease characterized by undesired production of protein comprising contacting said animal with a compound of claim 16. 50. A method of treating an animal having a disease characterized by undesired production of protein comprising contacting said animal with a compound of claim 24. 51. A method of treating an animal having a disease characterized by undesired production of protein comprising contacting said animal with a compound of claim 32. 52. A method of treating an animal having a disease characterized by undesired production of protein comprising contacting said animal with a compound of claim 37. 53. A method for detecting the presence or absence of an RNA in a biological sample suspected of containing said RNA comprising contacting said sample with a compound of claim 1. 54. A method for detecting the presence or absence of an RNA in a biological sample suspected of containing said RNA comprising contacting said sample with a compound of claim 9. 55. A method for detecting the presence or absence of an RNA in a biological sample suspected of containing said RNA comprising contacting said sample with a compound of claim 16. 56. A method for detecting the presence or absence of an RNA in a biological sample suspected of containing said RNA comprising contacting said sample with a compound of claim 24. 57. A method for detecting the presence or absence of an RNA in a biological sample suspected of containing said RNA comprising contacting said sample with a compound of claim 32. 58. A method for detecting the presence or absence of an RNA in a biological sample suspected of containing said RNA comprising contacting said sample with a compound of claim 37.

Inventors: COOK PHILLIP DAN, MANOHARAN MUTHIAH, COOK, PHILLIP, DAN, MANOHARAN, MUTHIAH
Applicants: ISIS PHARMACEUTICALS INC, ISIS PHARMACEUTICALS, INC.
Application year: 1994
Main classification: A61K31
IPC codes: C07C323, C07H19, C07H21, C07H23, C07J31, C07J43, C07J51, C12N15, C12Q1